Multicomponent Heterocyclic Chemistry for Undergraduate OrganicLaboratory: Biginelli Reaction with Multiple UnknownsFehmi Damkaci* and Adam Szymaniak

Department of Chemistry, State University of New York at Oswego, Oswego, New York 13126, United States

*S Supporting Information

ABSTRACT: Multicomponent reactions and heterocyclic chemistry areimportant concepts of organic synthesis, especially in the pharmaceuticalindustry. A one-pot, multicomponent Biginelli condensation reaction tosynthesize dihydropyrimidine derivatives from multiple unknowns isinvestigated as a discovery-based experiment in a second semester, second-year undergraduate organic chemistry laboratory course. Three 1,3-dicarbonylcompounds, two aryl aldehydes, and urea are utilized to provide six differentunknown dihydropyrimidine derivatives with average yields ranging from 63−79%. Students identify their products using 1H NMR, 13C NMR, DEPT, andIR spectroscopic data. The experiment provides an opportunity to discussmulticomponent reactions, carbonyl condensations with amines, enolchemistry, and interpretation of spectra, while being completed in a 3-hlaboratory period.

KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives,Aldehydes, Amines, Heterocycles, IR Spectroscopy, NMR Spectroscopy, Synthesis

Due to its efficiency in accessing complex heterocyclicstructures in one step, multicomponent reactions

(MCRs)1 have been widely adapted in organic research andindustry. Following the same trend, the number of under-graduate organic laboratory experiments using MCRs2 has alsoincreased in recent years. MCRs have the advantage ofconserving most of the atoms from the building blocks thatare present in the product to generate libraries of compounds inan efficient manner. Therefore, MCRs can be used to introducethe concept of combinatorial chemistry as a tool utilized in drugdiscovery to the undergraduate laboratory curriculum.2e,3

The reaction of interest was the Biginelli reaction,4 a one-potcondensation of a 1,3-dicarbonyl compound, aryl aldehyde, andurea in the presence of a Lewis acid to form a dihydropyr-imidine (Scheme 1). Dihydropyrimidine derivatives show manymedicinal properties, such as calcium channel blocking,

antiviral, and antibacterial activities, and are an effective scaffoldfor subsequent additions.5 The experiment and the approachdiscussed herein have the pedagogical goals to developunderstanding of MCRs, combinatorial chemistry, acid-catalyzed condensations and the role of Lewis Acids, and todevelop the ability to determine an organic structure throughspectral analysis.The most widely accepted mechanism for the Biginelli

reaction, which is supported by Kappe’s experimentalevidence,4a involves an acid-catalyzed condensation ofbenzaldehyde and urea affording a hemiaminal, whichdehydrates to a key N-acyliminium ion intermediate.Subsequently, an enol form of ethyl acetoacetate attacks theN-acyliminium ion to generate an open chain ureide, whichreadily cyclizes to form the dihydropyrimidine product.For student laboratory use, Holden and Crouch developed a

microscale Biginelli synthesis that takes 1.5 h in the presence ofethanol and HCl with an average yield of 58%.2i Aktoudianakisand co-workers developed a solvent-free Biginelli synthesis thattakes 15 min in the presence of ZnCl2 with an average yield of65%.2f Both experiments utilized the condensation ofbenzaldehyde, ethyl acetoacetate, and urea to give a singleproduct.A discovery-based (the possible reactants are known, but the

specific reactants are unknown to students) Biginelli synthesiswith focus on MCRs is described where students synthesizeone of six different dihydropyrimidines (Table 1) when givenone of three known 1,3-dicarbonyl compounds and one of two

Scheme 1. Reaction Mechanism for the BiginelliCondensation Reaction

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known benzaldehydes. The reaction is carried out in thepresence of ytterbium(III) triflate using water and acetic acid assolvent at 95 °C for 15 min. From IR and 1H NMRspectroscopic data a student obtains on the product of thesynthesis and 13C NMR and DEPT spectroscopic data of theproduct provided (see Supporting Information), a studentidentifies the correct reactants from the product. Thisexperiment, designed for one 3-h laboratory period in thesecond semester, second-year undergraduate organic curricu-lum, provides an opportunity to discuss and review variousconcepts (enols, amines, aromatic compounds, heterocycliccompounds, carbonyl chemistry, multicomponent reactions,and spectral interpretation) taught in multiple chapters of atypical second-year organic chemistry course.

■ EXPERIMENTAL SECTIONStudents work individually. The reaction is carried out at the 4mmol level for the aryl aldehyde. Urea (2 equiv), 1,3-dicarbonylcompound (2 equiv), aryl aldehyde (1 equiv), and ytterbium-(III) triflate hydrate (0.1 equiv) are dissolved in acetic acid andwater solvent (3:1) in a reaction vial containing a magnetic stirbar. An oil bath is heated to 95 °C and the capped vial is kept inthe oil bath for 15 min. The reaction mixture is cooled to roomtemperature; the contents are poured onto ice and the productis precipitated with ice-cold water. The precipitate is collectedby vacuum filtration and washed with ice-cold water andtoluene under vacuum to remove residual acetic acid; thedihydropyrimidines are white, yellow, or orange solids. Eachstudent obtains an IR spectrum and submits a sample for 1HNMR analysis during the laboratory period. 13C NMR andDEPT data are provided for analysis.

■ HAZARDSEthyl acetoacetate causes eye and skin irritation, gastrointestinaland respiratory tract irritation with nausea, drowsiness, anddizziness. Methyl acetoacetate causes eye irritation and maycause skin, respiratory, and gastrointestinal tract irritation. 2,4-Pentanedione is a flammable liquid and vapor (flash point 34°C), causes eye irritation and skin irritation, and is harmful ifingested or inhaled. Benzaldehyde is a reducing agent,potentially causing a fire and explosion risk near oxidizingagents; it will cause eye and skin irritation and is harmful ifswallowed or inhaled. p-Tolualdehyde may cause skin, eye,respiratory, and gastrointestinal tract irritation. Urea may causeskin, eye, respiratory, and gastrointestinal tract irritation.

Ytterbium(III) trifluoromethanesulfonate hydrate causes eyeirritation and may be harmful if swallowed, inhaled, or absorbedthrough skin. Glacial acetic acid is a flammable liquid andcauses severe eye irritation and skin burns; it may be harmful ifinhaled or swallowed. Dimethyl sulfoxide-d6 is slightly hazard-ous in case of inhalation, of skin contact, of eye contact, and ofingestion. The hazards of the products are unknown, and allshould be handled as hazardous in case of inhalation, skincontact, eye contact, and ingestion. Eye protection and glovesmust be used throughout the entire experiment.

■ RESULTS AND DISCUSSIONThis experiment was run once by 15 students in a 3-hlaboratory period of a second-semester organic chemistrylaboratory course. The experiment setup and workup took 1.5h, and the remaining time was used to obtain and analyzespectral data. Students easily followed the procedure with allreactions going to completion; student yields ranged from 57%to 91%, with an average yield of 72% (Table 1). Products had apurity of 90% or higher, with acetic acid and water as majorimpurities, according to student 1H NMR spectra. Thepedagogical goals stated above were assessed by a postlabor-atory report (accuracy of structural determination and postlabquestions) and a laboratory final exam. Students were requiredto use the spectra of their dihydropyrimidine to identify thecorrect product and, thus, the unknown building blocks. Two ofthe 15 students did not correctly identify both the product andthe unknown building blocks. All students correctly answeredone final exam question describing MCRs and providing aconceptual reaction example.Overall, the feedback from students was extremely positive.

Comments included how they liked the straightforwardness ofthe experimental section, as well as the intrigue and challenge ofthe discovery-based approach. The Biginelli reaction productswere sufficiently complex to challenge students in identifyingthe structures using spectral data, a good feature of theexperiment, which was a comment by most students. Also,students commented how they thought it was exciting to readabout the medicinal activity of some dihydropyrimidines.

■ CONCLUSIONThe Biginelli reaction provided a good opportunity to reviewand reinforce numerous concepts from various organicchemistry chapters in one laboratory period. The short reactiontime and workup procedure prevented students from havingextended idle times for heating and time to becomedisinterested in the lab. Overall, this experiment was alsosuccessful in employing essential skills, such as spectralinterpretation and percent yield calculations, while stimulatingstudents with a synthesis of medicinally active dihydropyr-imidine products from unknown starting materials.

■ ASSOCIATED CONTENT*S Supporting Information

Instructions for students and instructors, and 1H NMR, 13CNMR, DEPT, and FT-IR spectra for all products. This materialis available via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: fehmi.damkaci@oswego.edu.

Table 1. Starting Materials and Products for BiginelliSynthesis

R1 R2 Average Student Yields (Ranges)

−OEt −H 63 (57−76%)−OMe −H 75 (69−77%)−Me −H 73 (68−91%)−OEt −Me 66 (64−69%)−OMe −Me 74 (71−76%)−Me −Me 79 (75−84%)

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Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

We would like to especially thank Kristin Gublo of SUNYOswego for all the help setting up the laboratory equipmentnecessary and Fred Scoles for the instrumental assistance. Wewould also like to thank the Provost, Lorrie Clemo, and theChemistry Department for providing funds.

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